Moving forward-the 2019 ASCCP Risk-Based Management
Transcript Of Moving forward-the 2019 ASCCP Risk-Based Management
UCSF
UC San Francisco Previously Published Works
Title Moving forward-the 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors and beyond: implications and suggestions for laboratories.
Permalink https://escholarship.org/uc/item/1195g2mc
Journal Journal of the American Society of Cytopathology, 9(4)
ISSN 2213-2945
Authors Nayar, Ritu Chhieng, David C Crothers, Barbara et al.
Publication Date 2020-07-01
DOI 10.1016/j.jasc.2020.05.002
Peer reviewed
eScholarship.org
Powered by the California Digital Library University of California
Journal of the American Society of Cytopathology (2020) xx, 1e13
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jascyto.org/
Moving forwarddthe 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors and beyond: implications and suggestions for laboratories
Ritu Nayar, MDa,*, David C. Chhieng, MDb, Barbara Crothers, DOc, Teresa M. Darragh, MDd, Diane D. Davey, MDe, Carol Eisenhut, MDf, Robert Goulart, MDg, Eric C. Huang, MD, PhDb, Sana O. Tabbara, MDh
a Department of Pathology and Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, Illinois b Department of Pathology, University of Washington, School of Medicine, Seattle, Washington c Joint Pathology Center, Silver Spring, Maryland d University of California, San Francisco, California e Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando, Florida f DCL Pathology, Indianapolis, Indiana g New England Pathology Associates, Trinity Health of New England, Springfield, Massachusetts h Department of Pathology, The George Washington University, Washington, District of Columbia
Received 6 May 2020; received in revised form 10 May 2020; accepted 11 May 2020
Pathology Society Representation* to the 2019 ASCCP Guidelines Effort: Cytopathology Education and Technology Consortium (CETC) - Ritu Nayar. American Society of Cytopathology (ASC) - Ritu Nayar, Sana O. Tabbara. College of American Pathologists (CAP) - Barbara Crothers, Teresa M. Darragh, Diane D. Davey. American Society for Clinical Pathology (ASCP) - Robert Goulart, Carol Eisenhut. Papanicolaou Society of Cytopathology (PSC) - Eric C. Huang, David C.
Chhieng. Pathologists on ASCCP Guidelines Steering Committee - Teresa M. Darragh, Ritu Nayar. *Note: The content of this paper represents the authors opinions, not necessarily that of the societies they represent. *Corresponding author: Ritu Nayar, MD; Northwestern Memorial Hospital, Galter 132-B 251 East Huron Street, Chicago, IL 60611; Tel.: 312 926 7008; Fax: 312 926 6037. E-mail address: [email protected] (R. Nayar).
2213-2945/$36 Ó 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jasc.2020.05.002
2
KEYWORDS ASCCP; Cervical cytology; HPV testing; Management of abnormal cervical cancer screening tests; Guidelines
R. Nayar et al.
The 2019 ASCCP Risk Based Management Consensus Guidelines for prevention of cervical cancer promote clinical management recommendations aligned with our increased understanding of HPV biology and cervical carcinogenesis. They employ HPVebased testing as the basis for risk estimation, allow for personalized risk-based management by incorporating knowledge of current results with prior results, and streamline incorporation of new test methods as they are validated. They continue to support the principles of “equal management for equal risk” and “balancing harms and benefits” adopted in the 2012 version of the guidelines. These updated guidelines will be able to adjust for decreasing CIN3þ risks as more patients who received HPV vaccination reach screening age. Pathology organizations were closely involved in the development of these guidelines. Herein the pathologists who served as representatives to the 2019 ASCCP guidelines steering committee and workgroups, summarize the changes that are relevant to laboratories, pathologists, and cytotechnologists. Prior relevant screening and reporting recommendations that have not been widely and/or inconsistently adopted by laboratories are also discussed and considerations for modification of laboratory practices offered.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Human papillomavirus (HPV) testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
HPV genotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Reporting and management of anatomic pathology results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Cytopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Atypical glandular cells (AGC) and adenocarcinoma in situ (AIS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Atypical squamous cells, cannot exclude HSIL (ASC-H) and combinations of cytology results . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Reporting of HPV-Associated squamous intraepithelial lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Reporting and management of histologic glandular lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 Adenocarcinoma in situ (AIS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 Newer glandular entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Pregnancy-related considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 Quality assurance: cytology-histology correlation and more . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Introduction
In 2012, screening and management guidelines for the prevention of cervical cancer adopted the principle of “equal management for equal risk”. Despite the variety of individual test results from different points in the screening and management of an individual, those with similar risks for precancer or cancer can be managed similarly.1 Since 2012, further risk data relevant to cervical cancer have accumulated and show that an individual’s risk of precancer is not dependent solely on their current test results, but may be significantly modified by other factors such as prior screening history, duration and genotype of a human papillomavirus (HPV) infection, and previous treatment for precancer.2-6 Newer approaches to screening and triage have been approved in the United States (eg, primary HPV screening; p16/Ki67 dual staining),7,8 and additional methods and new technologies are either in advanced development or seeking regulatory approval.
The 2012 ASCCP guidelines included 19 management algorithms. The guidelines were complex and did not fully incorporate the increasing understanding of an individual’s risk for cervical precancer. In 2017, the ASCCP, formerly the American Society of Colposcopy and Cervical Pathology, and the National Cancer Institute (NCI) entered into a memorandum of understanding to undertake the development of new risk-based management guidelines that would do just thisdincorporate the ability to consider individualized risk by taking into account current test results and past history when managing each patient.9-11 The 2019 ASCCP guidelines highlight that detection and treatment of precancer (high-grade squamous intraepithelial lesion [HSIL]/ cervical intraepithelial neoplasia [CIN]3) remains the main aim of cervical cancer prevention in the United States and that the management of patients with abnormal screening results can be optimized by identifying those with the highest risk while minimizing procedures with potential harms for those with low risk.12
2019 ASCCP cancer screening guidelines
A major goal of the 2019 ASCCP guidelines effort was to simplify the management guidelines, thereby clarifying appropriate tests and testing intervals. Risks were estimated by NCI statisticians using large population data sets in the United States.13 Kaiser Permanente Northern California is the largest, most comprehensive data set in the United States, although for the 2019 guidelines, additional databases were analyzed to ensure that results are applicable to patients of diverse racial, ethnic, and socioeconomic strata. Risk estimates were compared using screening and followup data from clinical trials (BD Onclarity registrational trials), the New Mexico State HPV Pap Registry, and the US Centers for Disease Control and Prevention's National Breast and Cervical Cancer Early Detection Program, a national program that includes many low-income and minority patients.14,15
The risk strata (ranges of risk for CIN 3þ) for the guidelines are defined by clinical action thresholds (CATs) that
3
were determined through the consensus process under the principle of “equal management for equal risk”. The immediate and 5-year cumulative risks of CIN 3þ were estimated for each combination of current test results and screening/ surveillance history (including unknown history). To determine the next step in management, the estimated risk for a given patient is compared with the proposed CATs (Fig. 1). Management options include return to routine screening, a shortened surveillance interval (1 year or 3 years), colposcopy, or treatment. Providers can use the 2019 ASCCP guidelines to manage their patients by using the tables in Egemen et al13 or by inputting patient results and history into either a new ASCCP mobile app or Web site designed to facilitate navigation of the tables available at http://www. asccp.org, including a no-cost version. Although there have been requests for integration of the 2019 ASCCP risk-based guidelines with the electronic medical record and laboratory reports, these options are not currently available.
Figure 1 This figure demonstrates how patient risk is evaluated. For a given current results and history combination, the immediate CIN 3þ risk is examined. If this risk is 4% or greater, immediate management via colposcopy or treatment is indicated. If the immediate risk is less than 4%, the 5-year CIN 3þ risk is examined to determine whether patients should return in 1, 3, or 5 years. Adapted with permission from Perkins et al.15
4
The following are examples of potential change to the 2012 “equal management for equal risk” principle of management that will resonate with pathologists as well as providers.
Previously, women with test results of atypical squamous cells of undetermined significance (ASC-US)/HPV-positive were managed with colposcopydhowever, based on the 2019 ASCCP guidelines, management may differ depending on prior history/HPV status.15 The 2019 ASCCP guidelines aim to decrease unnecessary procedures in lowrisk women. An example of risk-based management for the same result is illustrated here: An ASC-US HPV-positive result will have an immediate risk of CIN 3þ of 4.4% (exceeding the 4% colposcopy threshold) when the prior history is unknown. However, if the prior result was a negative HPV primary screen or cotest, the immediate CIN 3þ risk is 2% if, resulting in a 1-year HPV-based follow-up (Table 1A, Egemen D, et al).13 If the ASC-US/HPVpositive was followed by colposcopy with biopsy showing CIN1 the prior year, the negative colposcopy reduces the risk of CIN 3þ within the next 2 years, and the immediate risk of CIN 3þ would be 3.1%, also resulting in a 1-year HPV-based follow-up (Table 4A, Egemen D, et al).13
The New Technology Committee will continue to assess and implement updates as new tests become approved and available, providing an enduring platform for new developments to be incorporated and the ability for the 2019 ASCCP guidelines to be updated on a more regular basis, without a large consensus conference effort. Additional risk modifiers, such as HPV vaccination status, will also be added, as vaccinated cohorts in the United States enter screening age, and enough data accumulates.
A deliberative method of stakeholder engagement was utilized in the development of these consensus guidelines, with the inclusion of representatives from 19 stakeholder organizations in the guideline working groups. Input from a number of surveys of providers and patients, and feedback from an open public comment period on draft guidelines, were considered before finalizing the 2019 ASCCP guidelines.16 Pathologists were well represented by major professional organizations, with 11 pathologists distributed among the working groups and 2 on the steering committee. The 2019 ASCCP Risk-Based Consensus Management Guidelines rolled out on April 2, 2020 during the virtual ASCCP annual meeting.15
As laboratorians, how can we support cervical cancer prevention in view of the new screening and management guidelines? Herein we summarize the changes in the 2019 ASCCP guidelines that are relevant to laboratories, pathologists, and cytotechnologists. Prior relevant screening and reporting recommendations that have not been widely and/ or consistently adopted by laboratories are also discussed. We also offer considerations for modification of laboratory practices as we transition to these updated practice guidelines.
R. Nayar et al.
Human papillomavirus (HPV) testing
HPV has long been established as a necessary cause of cervical cancer.17 Over the past 3 decades, advances in our understanding of the pathobiology of HPV have clarified that it involves the anogenital tract epithelium in 2 distinct ways: HPV infection and true precancer. In the context of HPV testing for cervical cancer prevention, our goal is to detect those infections that may progress to precancer or cancer; hence, only testing platforms detecting high-risk or oncogenic types of HPV should be used. Low-risk types of HPV infection can cause external genital warts and are rarely, if ever, linked to cervical cancer or high-grade precursor lesions. Testing for low-risk HPV infections in the cervix does not provide information with regard to a patient’s risk status and/or impact patient management. In fact, identification of low-risk HPV infection may lead to additional unnecessary testing and procedures, which can result in patient harm. Thus, we recommend against testing for low-risk HPV types.
HPV testing was introduced into the repertoire for cervical cancer screening and management in the United States in the mid 1990s. The indications for HPV testing vary based on the specific clinical situation for each patient and include screening, triage, and surveillance. Use of high-risk HPV testing was endorsed in screening and management guidelines, initially as a triage test for the cytologic result of ASC-US (2001). Regulatory approvals for cotesting (2003), for post-colposcopic/post-treatment follow-up and risk stratification using partial genotyping (2006), and as a standalone primary screening option (2014) followed.
In 2018, the US Preventive Services Task Force endorsed primary HPV screening for women aged 30 to 65 years.7 The updated American Cancer Society guidelines, due to be released in summer 2020, are also likely to endorse primary HPV screening in the United States. Although the United States has not widely adopted primary HPV testing as a screening modality, this transition is currently underway. These ongoing updates to cervical cancer screening guidelines, both in the United States and internationally, have been based on the higher sensitivity of HPV-based screening, modeling studies, and data from a number of trials, both in the United States and internationally. Comparison of screening methods is not the primary subject of this publication; however, additional communications, including from the Cytopathology Education and Technology Consortium, discuss concerns regarding the approval and implementation of primary HPV screening as the preferred screening strategy, without the option of cotesting, in the current US opportunistic screening program.18-22
There are currently 5 HPV tests approved by the US Food and Drug Administration (FDA) for cytology and HPV cotesting and reflex indications: Qiagen Hybrid Capture (Gaithersburg, MD), Hologic Cervista and Hologic Aptima (Marlborough, MA), Roche cobas (Indianapolis,
Table 1 Comparison of the 5 FDA-approved HPV testing platforms.
Test
Hybrid capture II
Cervista
Manufacturer Year FDA approved for r
eflex HPV testing and HPV/Papanicolaou cotesting Year approved for primary screening
Qiagen 2001
N/A
Hologic 2009
N/A
Method Genotypes detected
DNA (non-PCR based) Signal amplification:
full genome probe 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, 68
DNA (non-PCR based) Signal amplification:
L1, E6, and E7 genes 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, 66, and 68
Clinical trial
Clinical validation Sensitivity for CIN 2/3 Specificity for CIN 2/3 Built-in internal control
ASC-US/LSIL Triage Study (ALTS), 2006 CAP
Extensive 63.6%-100% 6.2%-98.4% No
Cervista HPV HR
Limited 92.8%-100% e Yes (HIST2H2BE)
Abbreviations: N/A, not applicable; PCR, polymerase chain reaction. Adapted with permission from Salazar et al.24
Cobas Roche 2011
2014 (ThinPrep only) 2018 (ThinPrep and
SurePath) DNA (PCR based); Target
amplification: L1 gene target
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 with genotyping of 16 and 18
ATHENA
Limited 71.1%-99% 24%-86.2% Yes (ß-globin)
Aptima Gen Probe (Hologic) 2011
N/A
mRNA (PCR based); Target amplification: E6/E7 gene target
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68; genotyping as separate test (16, 18/45)
CLEAR trial
Limited 55.3%-100% 28.8%-99.2% Yes, an internal control
transcript (HPV16 E6/7 transcript) is added to each reaction at the target capture step
BD Onclarity Becton Dickinson 2018
2018 (SurePath only)
DNA (PCR based); Target amplification: E6/E7 gene target
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68; simultaneous, discrete identification of 16, 18, and 45
Onclarity trial (baseline phase)
Limited 85.7%-100% 17%-98.8% Yes (ß-globin)
5
2019 ASCCP cancer screening guidelines
6
IN), and Becton Dickinson Onclarity (Franklin Lakes, NJ). All of these tests, except Aptima, utilize DNA hybridization and amplification or signal amplification. The Aptima test uses RNA amplification and some studies suggest that it is slightly more specific for high-grade precancers and cancers.23 All, except Qiagen’s HC2, have an internal control; however, none of the internal controls specifically identify epithelial cells. Only 2 of these platforms are approved for primary screening: cobas and Onclarity. The 2015 ASCCP interim and new (2019) guidelines, along with the Cytopathology Education and Technology Consortium, recommend that only platforms approved for primary screening be used when HPV testing alone is performed as a follow-up test strategy for women with a history of abnormal screening tests.15,22 Table 1 summarizes the characteristics of the FDA-approved HPV testing platforms currently available in the United States.24
In the 2019 ASCCP risk-based management consensus guidelines, HPV-based testing is the basis for risk estimation and laboratories will likely see a larger volume of HPV testing requests.13,14 The term HPV-based testing is used in the 2019 ASCCP guidelines to refer to use of either primary HPV testing alone or HPV testing in conjunction with cervical cytology (cotesting).15 Previously, HPV testing had mostly been used for cotesting or as a reflex test for an ASC-US cytology.
The 2019 ASCCP management guidelines15 specifically state:
Human papillomavirus assays that are Food and Drug Administration (FDA)-approved for screening should be used for management according to their regulatory approval in the United States. (Note: all HPV testing in this document refers to testing for high-risk HPV types only).
For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should only be used as a cotest with cytology, unless sufficient, rigorous data are available to support use of these particular tests in management.
Surveillance with cytology alone is acceptable only if testing with HPV or cotesting is not feasible. Cytology is less sensitive than HPV testing for detection of precancer and is therefore recommended more often.
HPV genotyping
The 2019 ASCCP guidelines incorporate partial genotyping (HPV 16/18) information, if available, in the risk assessment profile for patients who test positive for high-risk HPV types. This guidelines consensus effort acknowledged that not all laboratories may currently have genotyping capability; however, when available, this additional information further stratifies risk.15 Large data sets analyzed as part of the guidelines review process show that the identification of HPV 16 clearly mandates consideration in clinical management of new abnormal screening results. HPV 18
R. Nayar et al.
positivity must be considered as a special situation because of an established disproportionate risk of invasive cancer.25
When HPV-based screening is performed, the 2019 ASCCP guidelines recommend that:
All positive primary HPV screening tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory specimen (eg, reflex cytology). This is a change from the 2015 ASCCP interim guidance for management of primary HPV screening results.22 Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy practice. For example, the CAT for expedited treatment is met for patients who test HPV-16 positive with HSIL cytology; this approach bypasses the intermediate step of colposcopic biopsy confirmation of high-grade disease. If HPV 16 or 18 testing is positive, and additional laboratory testing of the same sample is not feasible, the patient should proceed directly to colposcopy.
HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (eg, colposcopy with biopsy) is necessary even when cytology results are negative or unavailable.
Laboratory requisitions and electronic medical records/ laboratory information system ordering options used at this time are likely to have been developed predominantly for HPV cotesting and reflex testing. Cytopathology professionals and laboratories should be prepared to facilitate testing strategies recommended in the 2019 ASCCP guidelines by assessing the following:
(a) Ability to identify and confirm primary versus cotest HPV testing requests in a clinical context.
(b) Ability to offer FDA-approved primary HPV screening and genotyping platforms.
(c) Testing options/order sets and workflow for HPV based screening/management options within the cytopathology laboratory and other locations (eg, molecular diagnostics/referred testing).
(d) Integrated reporting of results (preferred), when both HPV and cytology are utilized, whether as cytology/reflex HPV, cotesting, or primary HPV/reflex cytology and irrespective of the test indication (screening, triage or management).
(e) Electronic medical record clinical decision support implementation, especially passive clinical decision support, to guide age-compliant screening and triage options and support clinical providers.
Clinical providers are equally obligated to provide accurate and sufficient patient history on the requisition form to allow the laboratory to make certain that HPV test orders are consistent with the 2019 ASCCP guidelines. Providers should also ascertain that the HPV testing platform being utilized by their laboratory is FDA-approved for the specific test indication. Cytopathology professionals and laboratories should discuss
2019 ASCCP cancer screening guidelines
HPV testing platforms with clinicians and monitor compliance with age-specific screening and risk-based management guidelines and provide feedback to their clinician groups.
Reporting and management of anatomic pathology results
Cytopathology
Atypical glandular cells (AGC) and adenocarcinoma in situ (AIS) The Bethesda System (TBS) 2001 update replaced the term “atypical glandular cells of undetermined significance” (AGUS) with the term atypical glandular cells (AGC), and recommended a 2-tiered subcategorization: first, as to cell type/origin, if possible (ie, endocervical versus endometrial, or glandular when uncertain), and second, as favor neoplasia or not otherwise specified (NOS) for AGC and atypical endocervical cells (AEC). The rubric of AGC also includes atypical endometrial cells. Although cervical cytology is not a screening test for endometrial pathology, lesional cells can sometimes be seen. Atypical endometrial cells are not further subcategorized in terms of risk of neoplasia. TBS 2001 also introduced a specific cytologic interpretation of adenocarcinoma in situ (AIS).26 There were no changes made to the reporting categories for glandular epithelial cell abnormalities in TBS 2014.27
The overall category of AGC, albeit rare, may correspond histologically to several different entities ranging from benign (eg, polyps, tubal metaplasia) to intraepithelial lesions and invasive cancer, and include both glandular and squamous lesions (eg, HSIL involving endocervical glands, AIS, invasive adenocarcinoma of the Mullerian tract or other sites).28 AGC is a much higherrisk cytologic interpretation than ASC-US. Even with established TBS diagnostic criteria, cytologic glandular abnormalities remain poorly reproducible and diagnostically challenging; this results in both under- and overinterpretation by cytotechnologists and cytopathologists.29,30 Some laboratories target AGC cases for consensus review by additional pathologists prior to issuing a final report.
The 2019 ASCCP guidelines for glandular cytologic abnormalities remain similar to the 2012 guidelines. Clinicians and cytologists often incorrectly think of cytologic AGC as a group with the same management. Triage of any category of AGC by HPV testing continues to be unacceptable in the 2019 ASCCP guidelines. All cytologic glandular abnormalities will lead to initial colposcopic evaluation with endocervical sampling except when atypical endometrial cells are specified. In that case, the preferred initial evaluation is endometrial and endocervical sampling. Additional endometrial sampling is also recommended when the patient is 35 years of age or older, symptomatic, or at high risk for endometrial neoplasia
7
based on risk factors. The 2019 ASCCP guidelines emphasize that although endometrial cancer is rare in premenopausal patients without risk factors, the prevalence of premenopausal endometrial cancer is increasing, underscoring the importance of endometrial sampling when indicated. Subsequent management for cytologic AEC/AGC, favor neoplasia and AIS is a diagnostic excision procedure, even if a high-grade abnormality is not confirmed on colposcopic biopsy with endocervical sampling, and even if HPV testing is negative. As endocervical lesions are difficult to visualize clinically, colposcopists rely on pathologists to provide appropriate categorization of cell origin and level of suspicion for neoplasia so that appropriate management is possible.31
Atypical squamous cells, cannot exclude HSIL (ASC-H) and combinations of cytology results According to the Kaiser Permanente Northern California data, HPV-negative atypical squamous cells, cannot exclude HSIL (ASC-H) and HPV-positive ASC-H had very different CIN 3þ rates, but similar cancer rates. HPV-positive ASCH had an immediate CIN 3þ risk of 26% and a cancer risk of 0.92%, whereas HPV-negative ASC-H had an immediate CIN 3þ risk of 3.4%, but an immediate cancer risk of 0.69%. Because the immediate cancer risk for ASC-H is disproportionately high compared with the CIN 3þ risk, the 2019 guidelines carried forward the 2012 recommendations of colposcopy for all patients with ASC-H, regardless of HPV test results.15
HSIL found in the background of atrophy is often difficult to appreciate because of the lack of maturation of squamous cells and the similarity between small atrophic cells and the dysplastic cells. Additionally, as illustrated in the 2014 Bethesda Atlas, isolated highly atypical squamous cells, with very large nuclei, a characteristic smudgy or degenerative chromatin pattern, and a very high nucleus to cytoplasmic ratio can be occasionally identified in deeply atrophic specimens.26 Such cells can elicit morphologic concern for HSIL but are observed, often in older patients with few or no risk factors. A conservative approach, such as interpretation as ASC-US with follow-up/reflex HPV testing, rather than ASC-H, may be more appropriate in such cases. In cases of atrophy with abnormal cells meeting criteria for HSIL, however, an interpretation of HSIL should be made.
When reporting squamous intraepithelial lesions (SIL) according to Bethesda terminology, it is important to recognize that the concurrent presence of LSIL cells is not necessary to make an interpretation of HSIL and the presence of even a small population of definitive HSIL cells in the background of a predominance of LSIL cells should result in an interpretation of HSIL.27 In rare cases, cytology specimens may exhibit squamous cells with features that lie between low- and high-grade SIL. These include cases that exhibit predominantly LSIL and a few cells suggestive, but not diagnostic, of HSIL (ASC-H) or cases that display
8
keratinized cells with dense eosinophilic cytoplasm that give an impression of higher nucleus to cytoplasmic ratio than in classic LSIL, but without specific features of classic HSIL.27 Per TBS 2014, such cases should be reported using wellestablished TBS categories, specifically “ASC-H in a background of LSIL”, and not in other terms such as “LSIL, cannot exclude a high-grade lesion”.27
Non-TBS reporting terms do not provide clear management direction to the clinical provider, since they are not linked to the ASCCP management guidelines as are the TBS categories. Management under the 2019 ASCCP guidelines is based on the highest-risk cytologic interpretation, for example, ASC-H, when both ASC-H and LSIL are reported on the same sample. In other rare combinations of cytologic results such as HSIL and AGC, or ASC-US and AGC, management is also determined by the highest risk abnormality.15,27
Histopathology
Reporting of HPV-Associated squamous intraepithelial lesions Both the Lower Anogenital Squamous Terminology (LAST) Project32 and the World Health Organization33 recommend the use of a 2-tiered nomenclature for HPVassociated squamous cervical lesions: LSIL, the morphologic representation of HPV infection, and HSIL, the histopathological correlate of precancer. Rather than the spectrum of disease that is implied by the 3-tiered CIN classification system, the 2-tiered system of LSIL/HSIL better reflects the known biology of HPV disease. Both LAST and WHO also permit the CIN grade to be designated in parenthesis after the SIL nomenclature. Adoption of this terminology by pathologists has not been universal.
The 2019 ASCCP guidelines include the following specific statement regarding the use of p16 immunohistochemistry (IHC) and a 2-tiered nomenclature for reporting histopathology of HPV-associated squamous lesions of the lower anogenital tract.15
It is important to use p16 immunohistochemical staining according to the guidance provided by the College of American Pathologists (CAP)-ASCCP Lower Anogenital Squamous Terminology (LAST) Project. p16 immunohistochemistry should be used for specific indications as recommended by the LAST guidelines when interpreting the hematoxylin and eosin (H&E) slide. A positive p16 immunostain supports the diagnosis of histologic HSIL if the morphological assessment of H&E slides is consistent with CIN 2 or CIN 3. There is a risk of overcalling cervical histology findings when p16 is used incorrectly. Most importantly, a morphologic CIN1 on H&E should not be upgraded to histologic HSIL (CIN 2), even if p16 positive.
For epidemiologic and clinical management purposes, it is strongly recommended to qualify a histologic HSIL
R. Nayar et al.
result by CIN 2 or CIN 3, according to the options given by the LAST guidelines (eg, histologic HSIL [CIN 2]).
Rationale. This CIN qualification can have clinical importance (eg, to identify cases of CIN 2 in patients for whom conservative management is an acceptable option). It is also important for post-vaccine surveillance studies and quality control assessments of cervical precancer that have historically relied on CIN 2 and CIN 3 endpoints. Furthermore, it is important for future research efforts to distinguish diagnoses of histologic HSIL (CIN 2) from HSIL (CIN 3) so that diagnostic categories are compatible with the histologic endpoints used for current guidelines.
Note. Strong and diffuse block staining for p16, as defined by LAST32 is “continuous strong nuclear or nuclear plus cytoplasmic staining of the basal cell layer with extension upward involving at least one third of the epithelial thickness”. The latter height restriction is somewhat arbitrary but adds specificity. Full-thickness staining or extension into the upper third or upper half is specifically not required to call a p16 immunostain positive. Focal or patchy staining is nonspecific and can be seen with reactive squamous metaplasia, as well as low-grade disease (LSIL, CIN 1). All other staining patterns, described as cytoplasmic only, wispy, scattered, single cells, and others, are defined as negative.
It is important for pathologists to remember that p16 IHC is not a highly specific test34 and thus to use p16 only as suggested by the LAST recommendations to avoid overusage. As with other immunostains, correct interpretation of p16 IHC is also needed to avoid over interpretation of positivity. The LAST recommendations are undergoing an update, starting in 2020, and additional biomarkers could possibly further refine morphologic interpretations.
The 2019 ASCCP guidelines15 recommend treatment of histologic HSIL in most circumstances in non-pregnant women. Treatment is specifically recommended for HSIL (CIN 3), for any HSIL if the proximal extent of the lesion is in the endocervical canal or the entire squamocolumnar junction cannot be visualized, or if endocervical sampling shows HSIL or ungraded CIN. Treatment is also recommended for HSIL not further qualified (ie, CIN 2/3). Observation is preferred only when HSIL is specifically qualified as CIN 2 and only in specific situations: for women <25 years or for women whose concerns about pregnancy-related treatment complications outweigh concerns about cancer. Thus, a pathology report of cervical HSIL, regardless of CIN grade or unqualified, serves as the foundation for treatment decisions in most situations.
Given that background, how can pathologists give the most reliable histopathology diagnoses for cervical biopsies to their clinical colleagues to facilitate sound patient management recommendations? Any morphologic interpretation is subject to interobserver variation. Pathologists give more consistent diagnoses on cervical biopsies with the judicious
2019 ASCCP cancer screening guidelines
use of p16 IHC. Improved interobserver agreement for the diagnosis of CIN 2þ with the conjunctive use of hematoxylin and eosin (H&E) morphology and p16 IHC compared with H&E morphology alone has been shown in several studies,35-38 including in a systematic review and meta-analysis.39 Because histologic HSIL is the usual trigger for treatment, the use of p16 per the LAST and WHO guidelines provides our clinical colleagues more reproducible diagnoses upon which to base management recommendations.
The LAST Project recommends that p16 IHC, when positive, should be used to support the diagnostic interpretation of HSIL in times of diagnostic uncertainty (such as with atypical squamous metaplasia on H&E) and to support a diagnosis of HSIL (CIN 2). CIN 2 has historically been and remains the threshold for treatment in most circumstances. However, among pathologists, CIN 2 is the least reproducible of the CIN categories.40,41 If a diagnosis of CIN 2 is entertained based on solid morphologic criteria, a p16 should be performed to support a high-grade lesion. If negative, the diagnosis should be downgraded to LSIL or a benign process depending on the differential diagnosis on H&E. Judicious use of p16, in conjunction with H&E morphology is needed, however. When the morphologic diagnosis is LSIL (CIN 1), a p16 should not be performed. Morphologic LSIL (CIN 1) is frequently p16-positive; thus if p16 is positive, LSIL should not be upgraded to HSIL. There is insufficient data to indicate that the risk profile of p16-positive LSIL meets the CAT for treatment. Given diagnostic uncertainty encountered in tissue diagnoses of challenging histomorphology and the inherent interobserver variability of morphologic diagnosis, p16 IHC, when positive, is a useful tool to support a diagnosis of precancer.
More high-grade lesions may be identified as clinicians adopt the ASCCP colposcopy standards published in 2017.42 These standards recommend that colposcopists take multiple biopsies of all areas with acetowhitening, metaplasia, or higher colposcopic abnormalities. As a result, many colposopic procedures will have at least 2 and up to 4 targeted biopsies from distinct lesions. This recommendation should help reduce sampling issues related to colposcopic-directed biopsies and interobserver variability of colposopic impression of lesion grade, but it may also detect more small lesions that are morphologically highgrade.
An important and potentially overlooked issue is that of the size of the cervical HSIL. Lesion size is not a component of the treatment algorithms; treatment recommendations are based on the histopathology diagnosis of a potential precancer regardless of lesion size. In the only known and now infamous “Unfortunate Experiment”, an observational study of untreated CIN 3, the long-term risk of developing invasive cancer was approximately 30% over a 30-year period.43 As Schiffman and Rodriguez accurately point out in an accompanying commentary, these were large, prevalent lesions in women with a median age of 38 years.44 The
9
natural history of early, small lesions, potentially detected only because of increased sampling and screening efforts, remains unknown.
Another issue is the inability to accurately grade a fragmented squamous intraepithelial lesion (SIL), which is often reported as SIL, ungraded. Newer cervical biopsy collection devices, such as the SoftBiopsy, (Histologics Anaheim, CA; https://histologics.com/softbiopsy.html) and endocervical curettage specimens “denude” the cervical epithelium for tissue examination rather than provide a full-thickness tissue biopsy. This can result in problems with tissue orientation that make the lesion difficult to grade. These cases are more likely to result in a diagnosis of “SIL, ungraded”. A recent study by Lee et al45 found that histologic SIL, ungraded, although representing only 1.9% of their total cases, resulted in positive results (HSIL, AIS, or carcinoma) in 41% of patients with histologic follow-up. They found that a combination of p16 and ki-67 helped to correctly classify these lesions. Many clinical care providers do not understand that ungraded SIL represents a high-risk category for precancer and patients may not undergo sufficient followup; thus, laboratories are encouraged to communicate the possibility of HSIL or other significant abnormality in their reports.
Reporting and management of histologic glandular lesions
Adenocarcinoma in situ (AIS) The Society of Gynecologic Oncology (SGO) recently completed guidelines on the management of AIS and the 2019 ASCCP risk-based management consensus guidelines for glandular lesions are harmonized with the SGO guidelines.46 The only additional SGO-specific recommendation for management of an abnormal HPV-based screen result is that endocervical sampling is acceptable for any patient who tests positive for HPV 18 because of the high rate of HPV 18-positive AIS.
A diagnostic excisional procedure is recommended for all patients with a diagnosis of AIS on cervical biopsy to rule out invasive adenocarcinoma, even if hysterectomy is planned. The guidelines do not specifically recommend cold knife conization over loop electrocautery excisional procedure (LEEP), but do state that excisional procedures should aim to remove an intact specimen for evaluation of margin status by the pathologists. Hence, performance of a LEEP followed by a “top hat” endocervical excision is not acceptable. Ultimately, hysterectomy remains the preferred management for all patients with histologic AIS, but a fertility-sparing procedure is considered acceptable in select patients. Hysterectomy is preferred for AIS because it is often located within the endocervical canal, and is difficult to recognize on colposcopy, thus making decision on the extent of excision difficult. AIS is also known to have a higher risk of being multifocal, so negative margins on an
UC San Francisco Previously Published Works
Title Moving forward-the 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors and beyond: implications and suggestions for laboratories.
Permalink https://escholarship.org/uc/item/1195g2mc
Journal Journal of the American Society of Cytopathology, 9(4)
ISSN 2213-2945
Authors Nayar, Ritu Chhieng, David C Crothers, Barbara et al.
Publication Date 2020-07-01
DOI 10.1016/j.jasc.2020.05.002
Peer reviewed
eScholarship.org
Powered by the California Digital Library University of California
Journal of the American Society of Cytopathology (2020) xx, 1e13
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jascyto.org/
Moving forwarddthe 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors and beyond: implications and suggestions for laboratories
Ritu Nayar, MDa,*, David C. Chhieng, MDb, Barbara Crothers, DOc, Teresa M. Darragh, MDd, Diane D. Davey, MDe, Carol Eisenhut, MDf, Robert Goulart, MDg, Eric C. Huang, MD, PhDb, Sana O. Tabbara, MDh
a Department of Pathology and Northwestern Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, Illinois b Department of Pathology, University of Washington, School of Medicine, Seattle, Washington c Joint Pathology Center, Silver Spring, Maryland d University of California, San Francisco, California e Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando, Florida f DCL Pathology, Indianapolis, Indiana g New England Pathology Associates, Trinity Health of New England, Springfield, Massachusetts h Department of Pathology, The George Washington University, Washington, District of Columbia
Received 6 May 2020; received in revised form 10 May 2020; accepted 11 May 2020
Pathology Society Representation* to the 2019 ASCCP Guidelines Effort: Cytopathology Education and Technology Consortium (CETC) - Ritu Nayar. American Society of Cytopathology (ASC) - Ritu Nayar, Sana O. Tabbara. College of American Pathologists (CAP) - Barbara Crothers, Teresa M. Darragh, Diane D. Davey. American Society for Clinical Pathology (ASCP) - Robert Goulart, Carol Eisenhut. Papanicolaou Society of Cytopathology (PSC) - Eric C. Huang, David C.
Chhieng. Pathologists on ASCCP Guidelines Steering Committee - Teresa M. Darragh, Ritu Nayar. *Note: The content of this paper represents the authors opinions, not necessarily that of the societies they represent. *Corresponding author: Ritu Nayar, MD; Northwestern Memorial Hospital, Galter 132-B 251 East Huron Street, Chicago, IL 60611; Tel.: 312 926 7008; Fax: 312 926 6037. E-mail address: [email protected] (R. Nayar).
2213-2945/$36 Ó 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jasc.2020.05.002
2
KEYWORDS ASCCP; Cervical cytology; HPV testing; Management of abnormal cervical cancer screening tests; Guidelines
R. Nayar et al.
The 2019 ASCCP Risk Based Management Consensus Guidelines for prevention of cervical cancer promote clinical management recommendations aligned with our increased understanding of HPV biology and cervical carcinogenesis. They employ HPVebased testing as the basis for risk estimation, allow for personalized risk-based management by incorporating knowledge of current results with prior results, and streamline incorporation of new test methods as they are validated. They continue to support the principles of “equal management for equal risk” and “balancing harms and benefits” adopted in the 2012 version of the guidelines. These updated guidelines will be able to adjust for decreasing CIN3þ risks as more patients who received HPV vaccination reach screening age. Pathology organizations were closely involved in the development of these guidelines. Herein the pathologists who served as representatives to the 2019 ASCCP guidelines steering committee and workgroups, summarize the changes that are relevant to laboratories, pathologists, and cytotechnologists. Prior relevant screening and reporting recommendations that have not been widely and/or inconsistently adopted by laboratories are also discussed and considerations for modification of laboratory practices offered.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Human papillomavirus (HPV) testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
HPV genotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Reporting and management of anatomic pathology results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Cytopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Atypical glandular cells (AGC) and adenocarcinoma in situ (AIS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Atypical squamous cells, cannot exclude HSIL (ASC-H) and combinations of cytology results . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Reporting of HPV-Associated squamous intraepithelial lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
Reporting and management of histologic glandular lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 Adenocarcinoma in situ (AIS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 Newer glandular entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
Pregnancy-related considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 Quality assurance: cytology-histology correlation and more . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Introduction
In 2012, screening and management guidelines for the prevention of cervical cancer adopted the principle of “equal management for equal risk”. Despite the variety of individual test results from different points in the screening and management of an individual, those with similar risks for precancer or cancer can be managed similarly.1 Since 2012, further risk data relevant to cervical cancer have accumulated and show that an individual’s risk of precancer is not dependent solely on their current test results, but may be significantly modified by other factors such as prior screening history, duration and genotype of a human papillomavirus (HPV) infection, and previous treatment for precancer.2-6 Newer approaches to screening and triage have been approved in the United States (eg, primary HPV screening; p16/Ki67 dual staining),7,8 and additional methods and new technologies are either in advanced development or seeking regulatory approval.
The 2012 ASCCP guidelines included 19 management algorithms. The guidelines were complex and did not fully incorporate the increasing understanding of an individual’s risk for cervical precancer. In 2017, the ASCCP, formerly the American Society of Colposcopy and Cervical Pathology, and the National Cancer Institute (NCI) entered into a memorandum of understanding to undertake the development of new risk-based management guidelines that would do just thisdincorporate the ability to consider individualized risk by taking into account current test results and past history when managing each patient.9-11 The 2019 ASCCP guidelines highlight that detection and treatment of precancer (high-grade squamous intraepithelial lesion [HSIL]/ cervical intraepithelial neoplasia [CIN]3) remains the main aim of cervical cancer prevention in the United States and that the management of patients with abnormal screening results can be optimized by identifying those with the highest risk while minimizing procedures with potential harms for those with low risk.12
2019 ASCCP cancer screening guidelines
A major goal of the 2019 ASCCP guidelines effort was to simplify the management guidelines, thereby clarifying appropriate tests and testing intervals. Risks were estimated by NCI statisticians using large population data sets in the United States.13 Kaiser Permanente Northern California is the largest, most comprehensive data set in the United States, although for the 2019 guidelines, additional databases were analyzed to ensure that results are applicable to patients of diverse racial, ethnic, and socioeconomic strata. Risk estimates were compared using screening and followup data from clinical trials (BD Onclarity registrational trials), the New Mexico State HPV Pap Registry, and the US Centers for Disease Control and Prevention's National Breast and Cervical Cancer Early Detection Program, a national program that includes many low-income and minority patients.14,15
The risk strata (ranges of risk for CIN 3þ) for the guidelines are defined by clinical action thresholds (CATs) that
3
were determined through the consensus process under the principle of “equal management for equal risk”. The immediate and 5-year cumulative risks of CIN 3þ were estimated for each combination of current test results and screening/ surveillance history (including unknown history). To determine the next step in management, the estimated risk for a given patient is compared with the proposed CATs (Fig. 1). Management options include return to routine screening, a shortened surveillance interval (1 year or 3 years), colposcopy, or treatment. Providers can use the 2019 ASCCP guidelines to manage their patients by using the tables in Egemen et al13 or by inputting patient results and history into either a new ASCCP mobile app or Web site designed to facilitate navigation of the tables available at http://www. asccp.org, including a no-cost version. Although there have been requests for integration of the 2019 ASCCP risk-based guidelines with the electronic medical record and laboratory reports, these options are not currently available.
Figure 1 This figure demonstrates how patient risk is evaluated. For a given current results and history combination, the immediate CIN 3þ risk is examined. If this risk is 4% or greater, immediate management via colposcopy or treatment is indicated. If the immediate risk is less than 4%, the 5-year CIN 3þ risk is examined to determine whether patients should return in 1, 3, or 5 years. Adapted with permission from Perkins et al.15
4
The following are examples of potential change to the 2012 “equal management for equal risk” principle of management that will resonate with pathologists as well as providers.
Previously, women with test results of atypical squamous cells of undetermined significance (ASC-US)/HPV-positive were managed with colposcopydhowever, based on the 2019 ASCCP guidelines, management may differ depending on prior history/HPV status.15 The 2019 ASCCP guidelines aim to decrease unnecessary procedures in lowrisk women. An example of risk-based management for the same result is illustrated here: An ASC-US HPV-positive result will have an immediate risk of CIN 3þ of 4.4% (exceeding the 4% colposcopy threshold) when the prior history is unknown. However, if the prior result was a negative HPV primary screen or cotest, the immediate CIN 3þ risk is 2% if, resulting in a 1-year HPV-based follow-up (Table 1A, Egemen D, et al).13 If the ASC-US/HPVpositive was followed by colposcopy with biopsy showing CIN1 the prior year, the negative colposcopy reduces the risk of CIN 3þ within the next 2 years, and the immediate risk of CIN 3þ would be 3.1%, also resulting in a 1-year HPV-based follow-up (Table 4A, Egemen D, et al).13
The New Technology Committee will continue to assess and implement updates as new tests become approved and available, providing an enduring platform for new developments to be incorporated and the ability for the 2019 ASCCP guidelines to be updated on a more regular basis, without a large consensus conference effort. Additional risk modifiers, such as HPV vaccination status, will also be added, as vaccinated cohorts in the United States enter screening age, and enough data accumulates.
A deliberative method of stakeholder engagement was utilized in the development of these consensus guidelines, with the inclusion of representatives from 19 stakeholder organizations in the guideline working groups. Input from a number of surveys of providers and patients, and feedback from an open public comment period on draft guidelines, were considered before finalizing the 2019 ASCCP guidelines.16 Pathologists were well represented by major professional organizations, with 11 pathologists distributed among the working groups and 2 on the steering committee. The 2019 ASCCP Risk-Based Consensus Management Guidelines rolled out on April 2, 2020 during the virtual ASCCP annual meeting.15
As laboratorians, how can we support cervical cancer prevention in view of the new screening and management guidelines? Herein we summarize the changes in the 2019 ASCCP guidelines that are relevant to laboratories, pathologists, and cytotechnologists. Prior relevant screening and reporting recommendations that have not been widely and/ or consistently adopted by laboratories are also discussed. We also offer considerations for modification of laboratory practices as we transition to these updated practice guidelines.
R. Nayar et al.
Human papillomavirus (HPV) testing
HPV has long been established as a necessary cause of cervical cancer.17 Over the past 3 decades, advances in our understanding of the pathobiology of HPV have clarified that it involves the anogenital tract epithelium in 2 distinct ways: HPV infection and true precancer. In the context of HPV testing for cervical cancer prevention, our goal is to detect those infections that may progress to precancer or cancer; hence, only testing platforms detecting high-risk or oncogenic types of HPV should be used. Low-risk types of HPV infection can cause external genital warts and are rarely, if ever, linked to cervical cancer or high-grade precursor lesions. Testing for low-risk HPV infections in the cervix does not provide information with regard to a patient’s risk status and/or impact patient management. In fact, identification of low-risk HPV infection may lead to additional unnecessary testing and procedures, which can result in patient harm. Thus, we recommend against testing for low-risk HPV types.
HPV testing was introduced into the repertoire for cervical cancer screening and management in the United States in the mid 1990s. The indications for HPV testing vary based on the specific clinical situation for each patient and include screening, triage, and surveillance. Use of high-risk HPV testing was endorsed in screening and management guidelines, initially as a triage test for the cytologic result of ASC-US (2001). Regulatory approvals for cotesting (2003), for post-colposcopic/post-treatment follow-up and risk stratification using partial genotyping (2006), and as a standalone primary screening option (2014) followed.
In 2018, the US Preventive Services Task Force endorsed primary HPV screening for women aged 30 to 65 years.7 The updated American Cancer Society guidelines, due to be released in summer 2020, are also likely to endorse primary HPV screening in the United States. Although the United States has not widely adopted primary HPV testing as a screening modality, this transition is currently underway. These ongoing updates to cervical cancer screening guidelines, both in the United States and internationally, have been based on the higher sensitivity of HPV-based screening, modeling studies, and data from a number of trials, both in the United States and internationally. Comparison of screening methods is not the primary subject of this publication; however, additional communications, including from the Cytopathology Education and Technology Consortium, discuss concerns regarding the approval and implementation of primary HPV screening as the preferred screening strategy, without the option of cotesting, in the current US opportunistic screening program.18-22
There are currently 5 HPV tests approved by the US Food and Drug Administration (FDA) for cytology and HPV cotesting and reflex indications: Qiagen Hybrid Capture (Gaithersburg, MD), Hologic Cervista and Hologic Aptima (Marlborough, MA), Roche cobas (Indianapolis,
Table 1 Comparison of the 5 FDA-approved HPV testing platforms.
Test
Hybrid capture II
Cervista
Manufacturer Year FDA approved for r
eflex HPV testing and HPV/Papanicolaou cotesting Year approved for primary screening
Qiagen 2001
N/A
Hologic 2009
N/A
Method Genotypes detected
DNA (non-PCR based) Signal amplification:
full genome probe 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, 68
DNA (non-PCR based) Signal amplification:
L1, E6, and E7 genes 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59, 66, and 68
Clinical trial
Clinical validation Sensitivity for CIN 2/3 Specificity for CIN 2/3 Built-in internal control
ASC-US/LSIL Triage Study (ALTS), 2006 CAP
Extensive 63.6%-100% 6.2%-98.4% No
Cervista HPV HR
Limited 92.8%-100% e Yes (HIST2H2BE)
Abbreviations: N/A, not applicable; PCR, polymerase chain reaction. Adapted with permission from Salazar et al.24
Cobas Roche 2011
2014 (ThinPrep only) 2018 (ThinPrep and
SurePath) DNA (PCR based); Target
amplification: L1 gene target
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 with genotyping of 16 and 18
ATHENA
Limited 71.1%-99% 24%-86.2% Yes (ß-globin)
Aptima Gen Probe (Hologic) 2011
N/A
mRNA (PCR based); Target amplification: E6/E7 gene target
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68; genotyping as separate test (16, 18/45)
CLEAR trial
Limited 55.3%-100% 28.8%-99.2% Yes, an internal control
transcript (HPV16 E6/7 transcript) is added to each reaction at the target capture step
BD Onclarity Becton Dickinson 2018
2018 (SurePath only)
DNA (PCR based); Target amplification: E6/E7 gene target
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68; simultaneous, discrete identification of 16, 18, and 45
Onclarity trial (baseline phase)
Limited 85.7%-100% 17%-98.8% Yes (ß-globin)
5
2019 ASCCP cancer screening guidelines
6
IN), and Becton Dickinson Onclarity (Franklin Lakes, NJ). All of these tests, except Aptima, utilize DNA hybridization and amplification or signal amplification. The Aptima test uses RNA amplification and some studies suggest that it is slightly more specific for high-grade precancers and cancers.23 All, except Qiagen’s HC2, have an internal control; however, none of the internal controls specifically identify epithelial cells. Only 2 of these platforms are approved for primary screening: cobas and Onclarity. The 2015 ASCCP interim and new (2019) guidelines, along with the Cytopathology Education and Technology Consortium, recommend that only platforms approved for primary screening be used when HPV testing alone is performed as a follow-up test strategy for women with a history of abnormal screening tests.15,22 Table 1 summarizes the characteristics of the FDA-approved HPV testing platforms currently available in the United States.24
In the 2019 ASCCP risk-based management consensus guidelines, HPV-based testing is the basis for risk estimation and laboratories will likely see a larger volume of HPV testing requests.13,14 The term HPV-based testing is used in the 2019 ASCCP guidelines to refer to use of either primary HPV testing alone or HPV testing in conjunction with cervical cytology (cotesting).15 Previously, HPV testing had mostly been used for cotesting or as a reflex test for an ASC-US cytology.
The 2019 ASCCP management guidelines15 specifically state:
Human papillomavirus assays that are Food and Drug Administration (FDA)-approved for screening should be used for management according to their regulatory approval in the United States. (Note: all HPV testing in this document refers to testing for high-risk HPV types only).
For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should only be used as a cotest with cytology, unless sufficient, rigorous data are available to support use of these particular tests in management.
Surveillance with cytology alone is acceptable only if testing with HPV or cotesting is not feasible. Cytology is less sensitive than HPV testing for detection of precancer and is therefore recommended more often.
HPV genotyping
The 2019 ASCCP guidelines incorporate partial genotyping (HPV 16/18) information, if available, in the risk assessment profile for patients who test positive for high-risk HPV types. This guidelines consensus effort acknowledged that not all laboratories may currently have genotyping capability; however, when available, this additional information further stratifies risk.15 Large data sets analyzed as part of the guidelines review process show that the identification of HPV 16 clearly mandates consideration in clinical management of new abnormal screening results. HPV 18
R. Nayar et al.
positivity must be considered as a special situation because of an established disproportionate risk of invasive cancer.25
When HPV-based screening is performed, the 2019 ASCCP guidelines recommend that:
All positive primary HPV screening tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory specimen (eg, reflex cytology). This is a change from the 2015 ASCCP interim guidance for management of primary HPV screening results.22 Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy practice. For example, the CAT for expedited treatment is met for patients who test HPV-16 positive with HSIL cytology; this approach bypasses the intermediate step of colposcopic biopsy confirmation of high-grade disease. If HPV 16 or 18 testing is positive, and additional laboratory testing of the same sample is not feasible, the patient should proceed directly to colposcopy.
HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (eg, colposcopy with biopsy) is necessary even when cytology results are negative or unavailable.
Laboratory requisitions and electronic medical records/ laboratory information system ordering options used at this time are likely to have been developed predominantly for HPV cotesting and reflex testing. Cytopathology professionals and laboratories should be prepared to facilitate testing strategies recommended in the 2019 ASCCP guidelines by assessing the following:
(a) Ability to identify and confirm primary versus cotest HPV testing requests in a clinical context.
(b) Ability to offer FDA-approved primary HPV screening and genotyping platforms.
(c) Testing options/order sets and workflow for HPV based screening/management options within the cytopathology laboratory and other locations (eg, molecular diagnostics/referred testing).
(d) Integrated reporting of results (preferred), when both HPV and cytology are utilized, whether as cytology/reflex HPV, cotesting, or primary HPV/reflex cytology and irrespective of the test indication (screening, triage or management).
(e) Electronic medical record clinical decision support implementation, especially passive clinical decision support, to guide age-compliant screening and triage options and support clinical providers.
Clinical providers are equally obligated to provide accurate and sufficient patient history on the requisition form to allow the laboratory to make certain that HPV test orders are consistent with the 2019 ASCCP guidelines. Providers should also ascertain that the HPV testing platform being utilized by their laboratory is FDA-approved for the specific test indication. Cytopathology professionals and laboratories should discuss
2019 ASCCP cancer screening guidelines
HPV testing platforms with clinicians and monitor compliance with age-specific screening and risk-based management guidelines and provide feedback to their clinician groups.
Reporting and management of anatomic pathology results
Cytopathology
Atypical glandular cells (AGC) and adenocarcinoma in situ (AIS) The Bethesda System (TBS) 2001 update replaced the term “atypical glandular cells of undetermined significance” (AGUS) with the term atypical glandular cells (AGC), and recommended a 2-tiered subcategorization: first, as to cell type/origin, if possible (ie, endocervical versus endometrial, or glandular when uncertain), and second, as favor neoplasia or not otherwise specified (NOS) for AGC and atypical endocervical cells (AEC). The rubric of AGC also includes atypical endometrial cells. Although cervical cytology is not a screening test for endometrial pathology, lesional cells can sometimes be seen. Atypical endometrial cells are not further subcategorized in terms of risk of neoplasia. TBS 2001 also introduced a specific cytologic interpretation of adenocarcinoma in situ (AIS).26 There were no changes made to the reporting categories for glandular epithelial cell abnormalities in TBS 2014.27
The overall category of AGC, albeit rare, may correspond histologically to several different entities ranging from benign (eg, polyps, tubal metaplasia) to intraepithelial lesions and invasive cancer, and include both glandular and squamous lesions (eg, HSIL involving endocervical glands, AIS, invasive adenocarcinoma of the Mullerian tract or other sites).28 AGC is a much higherrisk cytologic interpretation than ASC-US. Even with established TBS diagnostic criteria, cytologic glandular abnormalities remain poorly reproducible and diagnostically challenging; this results in both under- and overinterpretation by cytotechnologists and cytopathologists.29,30 Some laboratories target AGC cases for consensus review by additional pathologists prior to issuing a final report.
The 2019 ASCCP guidelines for glandular cytologic abnormalities remain similar to the 2012 guidelines. Clinicians and cytologists often incorrectly think of cytologic AGC as a group with the same management. Triage of any category of AGC by HPV testing continues to be unacceptable in the 2019 ASCCP guidelines. All cytologic glandular abnormalities will lead to initial colposcopic evaluation with endocervical sampling except when atypical endometrial cells are specified. In that case, the preferred initial evaluation is endometrial and endocervical sampling. Additional endometrial sampling is also recommended when the patient is 35 years of age or older, symptomatic, or at high risk for endometrial neoplasia
7
based on risk factors. The 2019 ASCCP guidelines emphasize that although endometrial cancer is rare in premenopausal patients without risk factors, the prevalence of premenopausal endometrial cancer is increasing, underscoring the importance of endometrial sampling when indicated. Subsequent management for cytologic AEC/AGC, favor neoplasia and AIS is a diagnostic excision procedure, even if a high-grade abnormality is not confirmed on colposcopic biopsy with endocervical sampling, and even if HPV testing is negative. As endocervical lesions are difficult to visualize clinically, colposcopists rely on pathologists to provide appropriate categorization of cell origin and level of suspicion for neoplasia so that appropriate management is possible.31
Atypical squamous cells, cannot exclude HSIL (ASC-H) and combinations of cytology results According to the Kaiser Permanente Northern California data, HPV-negative atypical squamous cells, cannot exclude HSIL (ASC-H) and HPV-positive ASC-H had very different CIN 3þ rates, but similar cancer rates. HPV-positive ASCH had an immediate CIN 3þ risk of 26% and a cancer risk of 0.92%, whereas HPV-negative ASC-H had an immediate CIN 3þ risk of 3.4%, but an immediate cancer risk of 0.69%. Because the immediate cancer risk for ASC-H is disproportionately high compared with the CIN 3þ risk, the 2019 guidelines carried forward the 2012 recommendations of colposcopy for all patients with ASC-H, regardless of HPV test results.15
HSIL found in the background of atrophy is often difficult to appreciate because of the lack of maturation of squamous cells and the similarity between small atrophic cells and the dysplastic cells. Additionally, as illustrated in the 2014 Bethesda Atlas, isolated highly atypical squamous cells, with very large nuclei, a characteristic smudgy or degenerative chromatin pattern, and a very high nucleus to cytoplasmic ratio can be occasionally identified in deeply atrophic specimens.26 Such cells can elicit morphologic concern for HSIL but are observed, often in older patients with few or no risk factors. A conservative approach, such as interpretation as ASC-US with follow-up/reflex HPV testing, rather than ASC-H, may be more appropriate in such cases. In cases of atrophy with abnormal cells meeting criteria for HSIL, however, an interpretation of HSIL should be made.
When reporting squamous intraepithelial lesions (SIL) according to Bethesda terminology, it is important to recognize that the concurrent presence of LSIL cells is not necessary to make an interpretation of HSIL and the presence of even a small population of definitive HSIL cells in the background of a predominance of LSIL cells should result in an interpretation of HSIL.27 In rare cases, cytology specimens may exhibit squamous cells with features that lie between low- and high-grade SIL. These include cases that exhibit predominantly LSIL and a few cells suggestive, but not diagnostic, of HSIL (ASC-H) or cases that display
8
keratinized cells with dense eosinophilic cytoplasm that give an impression of higher nucleus to cytoplasmic ratio than in classic LSIL, but without specific features of classic HSIL.27 Per TBS 2014, such cases should be reported using wellestablished TBS categories, specifically “ASC-H in a background of LSIL”, and not in other terms such as “LSIL, cannot exclude a high-grade lesion”.27
Non-TBS reporting terms do not provide clear management direction to the clinical provider, since they are not linked to the ASCCP management guidelines as are the TBS categories. Management under the 2019 ASCCP guidelines is based on the highest-risk cytologic interpretation, for example, ASC-H, when both ASC-H and LSIL are reported on the same sample. In other rare combinations of cytologic results such as HSIL and AGC, or ASC-US and AGC, management is also determined by the highest risk abnormality.15,27
Histopathology
Reporting of HPV-Associated squamous intraepithelial lesions Both the Lower Anogenital Squamous Terminology (LAST) Project32 and the World Health Organization33 recommend the use of a 2-tiered nomenclature for HPVassociated squamous cervical lesions: LSIL, the morphologic representation of HPV infection, and HSIL, the histopathological correlate of precancer. Rather than the spectrum of disease that is implied by the 3-tiered CIN classification system, the 2-tiered system of LSIL/HSIL better reflects the known biology of HPV disease. Both LAST and WHO also permit the CIN grade to be designated in parenthesis after the SIL nomenclature. Adoption of this terminology by pathologists has not been universal.
The 2019 ASCCP guidelines include the following specific statement regarding the use of p16 immunohistochemistry (IHC) and a 2-tiered nomenclature for reporting histopathology of HPV-associated squamous lesions of the lower anogenital tract.15
It is important to use p16 immunohistochemical staining according to the guidance provided by the College of American Pathologists (CAP)-ASCCP Lower Anogenital Squamous Terminology (LAST) Project. p16 immunohistochemistry should be used for specific indications as recommended by the LAST guidelines when interpreting the hematoxylin and eosin (H&E) slide. A positive p16 immunostain supports the diagnosis of histologic HSIL if the morphological assessment of H&E slides is consistent with CIN 2 or CIN 3. There is a risk of overcalling cervical histology findings when p16 is used incorrectly. Most importantly, a morphologic CIN1 on H&E should not be upgraded to histologic HSIL (CIN 2), even if p16 positive.
For epidemiologic and clinical management purposes, it is strongly recommended to qualify a histologic HSIL
R. Nayar et al.
result by CIN 2 or CIN 3, according to the options given by the LAST guidelines (eg, histologic HSIL [CIN 2]).
Rationale. This CIN qualification can have clinical importance (eg, to identify cases of CIN 2 in patients for whom conservative management is an acceptable option). It is also important for post-vaccine surveillance studies and quality control assessments of cervical precancer that have historically relied on CIN 2 and CIN 3 endpoints. Furthermore, it is important for future research efforts to distinguish diagnoses of histologic HSIL (CIN 2) from HSIL (CIN 3) so that diagnostic categories are compatible with the histologic endpoints used for current guidelines.
Note. Strong and diffuse block staining for p16, as defined by LAST32 is “continuous strong nuclear or nuclear plus cytoplasmic staining of the basal cell layer with extension upward involving at least one third of the epithelial thickness”. The latter height restriction is somewhat arbitrary but adds specificity. Full-thickness staining or extension into the upper third or upper half is specifically not required to call a p16 immunostain positive. Focal or patchy staining is nonspecific and can be seen with reactive squamous metaplasia, as well as low-grade disease (LSIL, CIN 1). All other staining patterns, described as cytoplasmic only, wispy, scattered, single cells, and others, are defined as negative.
It is important for pathologists to remember that p16 IHC is not a highly specific test34 and thus to use p16 only as suggested by the LAST recommendations to avoid overusage. As with other immunostains, correct interpretation of p16 IHC is also needed to avoid over interpretation of positivity. The LAST recommendations are undergoing an update, starting in 2020, and additional biomarkers could possibly further refine morphologic interpretations.
The 2019 ASCCP guidelines15 recommend treatment of histologic HSIL in most circumstances in non-pregnant women. Treatment is specifically recommended for HSIL (CIN 3), for any HSIL if the proximal extent of the lesion is in the endocervical canal or the entire squamocolumnar junction cannot be visualized, or if endocervical sampling shows HSIL or ungraded CIN. Treatment is also recommended for HSIL not further qualified (ie, CIN 2/3). Observation is preferred only when HSIL is specifically qualified as CIN 2 and only in specific situations: for women <25 years or for women whose concerns about pregnancy-related treatment complications outweigh concerns about cancer. Thus, a pathology report of cervical HSIL, regardless of CIN grade or unqualified, serves as the foundation for treatment decisions in most situations.
Given that background, how can pathologists give the most reliable histopathology diagnoses for cervical biopsies to their clinical colleagues to facilitate sound patient management recommendations? Any morphologic interpretation is subject to interobserver variation. Pathologists give more consistent diagnoses on cervical biopsies with the judicious
2019 ASCCP cancer screening guidelines
use of p16 IHC. Improved interobserver agreement for the diagnosis of CIN 2þ with the conjunctive use of hematoxylin and eosin (H&E) morphology and p16 IHC compared with H&E morphology alone has been shown in several studies,35-38 including in a systematic review and meta-analysis.39 Because histologic HSIL is the usual trigger for treatment, the use of p16 per the LAST and WHO guidelines provides our clinical colleagues more reproducible diagnoses upon which to base management recommendations.
The LAST Project recommends that p16 IHC, when positive, should be used to support the diagnostic interpretation of HSIL in times of diagnostic uncertainty (such as with atypical squamous metaplasia on H&E) and to support a diagnosis of HSIL (CIN 2). CIN 2 has historically been and remains the threshold for treatment in most circumstances. However, among pathologists, CIN 2 is the least reproducible of the CIN categories.40,41 If a diagnosis of CIN 2 is entertained based on solid morphologic criteria, a p16 should be performed to support a high-grade lesion. If negative, the diagnosis should be downgraded to LSIL or a benign process depending on the differential diagnosis on H&E. Judicious use of p16, in conjunction with H&E morphology is needed, however. When the morphologic diagnosis is LSIL (CIN 1), a p16 should not be performed. Morphologic LSIL (CIN 1) is frequently p16-positive; thus if p16 is positive, LSIL should not be upgraded to HSIL. There is insufficient data to indicate that the risk profile of p16-positive LSIL meets the CAT for treatment. Given diagnostic uncertainty encountered in tissue diagnoses of challenging histomorphology and the inherent interobserver variability of morphologic diagnosis, p16 IHC, when positive, is a useful tool to support a diagnosis of precancer.
More high-grade lesions may be identified as clinicians adopt the ASCCP colposcopy standards published in 2017.42 These standards recommend that colposcopists take multiple biopsies of all areas with acetowhitening, metaplasia, or higher colposcopic abnormalities. As a result, many colposopic procedures will have at least 2 and up to 4 targeted biopsies from distinct lesions. This recommendation should help reduce sampling issues related to colposcopic-directed biopsies and interobserver variability of colposopic impression of lesion grade, but it may also detect more small lesions that are morphologically highgrade.
An important and potentially overlooked issue is that of the size of the cervical HSIL. Lesion size is not a component of the treatment algorithms; treatment recommendations are based on the histopathology diagnosis of a potential precancer regardless of lesion size. In the only known and now infamous “Unfortunate Experiment”, an observational study of untreated CIN 3, the long-term risk of developing invasive cancer was approximately 30% over a 30-year period.43 As Schiffman and Rodriguez accurately point out in an accompanying commentary, these were large, prevalent lesions in women with a median age of 38 years.44 The
9
natural history of early, small lesions, potentially detected only because of increased sampling and screening efforts, remains unknown.
Another issue is the inability to accurately grade a fragmented squamous intraepithelial lesion (SIL), which is often reported as SIL, ungraded. Newer cervical biopsy collection devices, such as the SoftBiopsy, (Histologics Anaheim, CA; https://histologics.com/softbiopsy.html) and endocervical curettage specimens “denude” the cervical epithelium for tissue examination rather than provide a full-thickness tissue biopsy. This can result in problems with tissue orientation that make the lesion difficult to grade. These cases are more likely to result in a diagnosis of “SIL, ungraded”. A recent study by Lee et al45 found that histologic SIL, ungraded, although representing only 1.9% of their total cases, resulted in positive results (HSIL, AIS, or carcinoma) in 41% of patients with histologic follow-up. They found that a combination of p16 and ki-67 helped to correctly classify these lesions. Many clinical care providers do not understand that ungraded SIL represents a high-risk category for precancer and patients may not undergo sufficient followup; thus, laboratories are encouraged to communicate the possibility of HSIL or other significant abnormality in their reports.
Reporting and management of histologic glandular lesions
Adenocarcinoma in situ (AIS) The Society of Gynecologic Oncology (SGO) recently completed guidelines on the management of AIS and the 2019 ASCCP risk-based management consensus guidelines for glandular lesions are harmonized with the SGO guidelines.46 The only additional SGO-specific recommendation for management of an abnormal HPV-based screen result is that endocervical sampling is acceptable for any patient who tests positive for HPV 18 because of the high rate of HPV 18-positive AIS.
A diagnostic excisional procedure is recommended for all patients with a diagnosis of AIS on cervical biopsy to rule out invasive adenocarcinoma, even if hysterectomy is planned. The guidelines do not specifically recommend cold knife conization over loop electrocautery excisional procedure (LEEP), but do state that excisional procedures should aim to remove an intact specimen for evaluation of margin status by the pathologists. Hence, performance of a LEEP followed by a “top hat” endocervical excision is not acceptable. Ultimately, hysterectomy remains the preferred management for all patients with histologic AIS, but a fertility-sparing procedure is considered acceptable in select patients. Hysterectomy is preferred for AIS because it is often located within the endocervical canal, and is difficult to recognize on colposcopy, thus making decision on the extent of excision difficult. AIS is also known to have a higher risk of being multifocal, so negative margins on an